Introduction

Uses for Byetta

Diabetes Mellitus

Used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.138

Available as an injection for twice-daily administration (Byetta)1 and as an extended-release for injectable suspension formulation for once-weekly administration (Bydureon).38

Exenatide has been used as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione; in combination with metformin and a sulfonylurea or thiazolidinedione; or in combination with insulin glargine with or without metformin and/or a thiazolidinedione.171623

Twice-daily exenatide improves glycemic control (e.g., as determined by changes in HbA1c) more than placebo and similar to that of titrated insulin lispro or insulin aspart 70/30.1162363

Extended-release exenatide has been used as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione; in combination with metformin and a sulfonylurea; or in combination with metformin and a thiazolidinedione.38

Once-weekly extended-release exenatide generally as effective for glycemic control as metformin or pioglitazone and more effective than sitagliptin, titrated insulin glargine, insulin detemir, or twice-daily exenatide;394041424547515253545758606162 such improvements maintained during long-term therapy.39464748495556576061

Extended-release exenatide not recommended as first-line therapy in patients with inadequate glycemic control on diet and exercise because of uncertain relevance to humans of thyroid C-cell tumors found in rodents given the drug.38 (See Boxed Warning.)

Exenatide or extended-release exenatide not a substitute for insulin.138

Do not use exenatide or extended-release exenatide in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis; not effective for these conditions.138

Safety and efficacy of exenatide or extended-release exenatide not established in patients with a history of pancreatitis; consider other antidiabetic agents in such patients.138 (See Pancreatitis and Pancreatic Precancerous Changes under Cautions.)

Safety and efficacy of exenatide in combination with prandial insulin not established; concomitant use not recommended.1

Safety and efficacy of extended-release exenatide in combination with insulin not established; such concomitant use not recommended.38

Exenatide and extended-release exenatide contain the same active ingredient; do not use both agents concomitantly.38

Byetta Dosage and Administration

Administration

Exenatide and extended-release exenatide intended for self-administration by patient.138 Healthcare professionals should instruct patients in preparation and use of drug before first use.122386970

Sub-Q Administration: Exenatide

Administer sub-Q into abdomen, thigh, or upper arm using prefilled injection pen.1 Safety and efficacy of IV or IM administration not established.1226667

Alternatively, administer before 2 main meals of the day, approximately ≥6 hours apart.114

Do not administer after a meal.114

If a dose is missed, omit that dose and administer next dose at regularly scheduled time.122

Do not transfer drug from injection pen to syringe or vial.1

Do not mix with insulin in same syringe or vial even if taken at same time.1226667

Consult manufacturer's instructions for use for additional details about preparation and administration of drug.1226667

Sub-Q Administration: Extended-release Exenatide

Administer sub-Q into abdomen, thigh, or back of upper arm region using prefilled injection pen; must not administer IV or IM.38686970 Rotate injection sites with each weekly dose when injecting in the same region.38686970

May administer at any time during dosing day, with or without a meal.3870

May change day of weekly administration if necessary, provided the last dose was administered at least 3 days previously.3870

If a dose is missed, administer missed dose as soon as noticed provided there are at least 3 days until the next scheduled dose; the usual regimen (once weekly) may then be resumed.3870

If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, do not administer the missed dose; instead, resume dosing on the next regularly scheduled day.3870

Consult manufacturer's instructions for use for additional details about preparation and administration of drug.38686970

Reconstitution

Supplied as sterile, white to off-white powder in prefilled single-use injection pens and in single-dose vials; must reconstitute before administration.3868

If injection pen has been stored in refrigerator, allow pen to stand at room temperature for 15 minutes before reconstitution.69

Diluent is contained in one compartment of injection pen with drug powder in another compartment; diluent for vial is supplied in a prefilled syringe within each single-dose tray.3868

Use diluent only if it is clear and free of visible particulate matter when viewed through prefilled syringe or injection window of pen.386869

Do not inject drug suspension until well mixed or full dose will not be delivered.6869

Reconstituted drug suspension in vial must be transferred to manufacturer-provided syringe before administration.68

Administer drug immediately after reconstitution; cannot store for later use.386970

Refer to manufacturer's instructions for use for detailed information regarding reconstitution.38686970

Dosage

If exenatide or extended-release exenatide used in combination with a sulfonylurea, reduction of sulfonylurea dosage may be required.12238 (See Use with Drugs Known to Cause Hypoglycemia under Cautions.)

If exenatide is used in combination with insulin, evaluate insulin dosage; consider reduction of insulin dosage in patients at increased risk of hypoglycemia.1 In a clinical trial, dosage of concomitant insulin glargine reduced by 20% in exenatide-treated patients with HbA1c concentrations ≤8%; 123 relative safety and efficacy of this approach may not apply to patients with baseline HbA1c concentrations <7%, those with a recent history of major hypoglycemia, or those receiving long-acting GLP-1 receptor agonists.23 (See Use with Drugs Known to Cause Hypoglycemia under Cautions.)

Safety and efficacy of extended-release exenatide and concomitant insulin therapy not established; not recommended by manufacturer.38

End-stage renal disease (ESRD) or severe renal impairment (Clcr <30 mL/minute): Do not use exenatide or extended-release exenatide.19122138 Use exenatide or extended-release exenatide with caution in patients who have undergone renal transplantation.138 (See Renal Effects and also Renal Impairment under Cautions.)

Geriatric Patients

Careful selection of exenatide dosage recommended due to possible age-related decrease in renal function and concomitant disease and drug therapy; however, dosage requirements generally similar in geriatric patients and younger adults.1 Use caution when initiating extended-release exenatide in geriatric patients.38

Obese Patients

Adjustment of exenatide dosage not required.1

Cautions for Byetta

Contraindications

Exenatide or extended-release exenatide: Known hypersensitivity to exenatide or any ingredient in the formulation.138

Refer patients to endocrinologist for further evaluation if thyroid nodules noted on physical examination or neck imaging.38

Although routine monitoring of serum calcitonin or use of thyroid ultrasound for early detection of MTC in patients receiving extended-release exenatide is of uncertain value, refer patient to endocrinologist for further evaluation if serum calcitonin is measured and found to be elevated.38

Pancreatitis and Pancreatic Precancerous Changes

Hallmark symptom of acute pancreatitis is persistent, severe abdominal pain, which sometimes radiates to the back and may be accompanied by vomiting.1 Most patients who developed pancreatitis during exenatide therapy had at least one other risk factor for acute pancreatitis (e.g., gallstones, severe hypertriglyceridemia, alcohol use) and required hospitalization.17 Serious complications include dehydration and renal failure, suspected ileus, phlegmon, and ascites; most patients have improved upon discontinuance of exenatide.17

After initiation of exenatide or extended-release exenatide, and after increases in dosage, carefully observe patients for signs and symptoms of acute pancreatitis (e.g., unexplained, persistent, severe abdominal pain that may radiate to the back; nausea; vomiting; elevated serum amylase or lipase concentrations).11738

FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cellular changes in patients with type 2 diabetes mellitus receiving incretin mimetics.3637 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when the agency has additional information to report.36

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.36 The manufacturer states that if pancreatitis is suspected, promptly discontinue therapy with exenatide or extended-release exenatide and other potentially suspected drugs, perform confirmatory tests (e.g., serum amylase or lipase concentrations, radiologic imaging), and initiate appropriate therapy.1172038

Do not resume exenatide or extended-release exenatide if pancreatitis confirmed.138

Safety and efficacy of exenatide or extended-release exenatide not established in patients with a history of pancreatitis; consider other antidiabetic therapies in such patients.138

Use with Drugs Known to Cause Hypoglycemia

Increased risk of hypoglycemia with exenatide or extended-release exenatide and concomitant sulfonylurea therapy; may require reduction of sulfonylurea dosage.138

If exenatide is used in combination with insulin, consider reduction of insulin dosage in patients at increased risk of hypoglycemia.1 (See Dosage under Dosage and Administration.) Safety and efficacy of exenatide in combination with prandial insulin or of extended-release exenatide with any type of insulin not established; concomitant use not recommended by manufacturer.138

Concomitant use of exenatide or extended-release exenatide with other glucose-independent insulin secretagogues (e.g., meglitinides) may increase risk of hypoglycemia.138

Renal Effects

Deterioration of renal function (e.g., increased Scr, renal impairment/insufficiency, worsened chronic renal failure, acute renal failure sometimes requiring hemodialysis or kidney transplantation) reported rarely.12138 In some patients, presence of other factors (nausea, vomiting, and/or diarrhea with or without dehydration; concomitant use of other agents known to affect renal function or hydration status [e.g., ACE inhibitors, NSAIAs, diuretics])12138 may have contributed to development of altered renal function.21

Exenatide not directly nephrotoxic in preclinical or clinical studies.138 Altered renal function may result from diabetes mellitus, independent of any risk associated with exenatide.21

Because exenatide or extended-release exenatide may induce nausea and vomiting with transient hypovolemia, this drug may worsen renal function.138

Closely monitor patients for signs and symptoms of renal dysfunction; consider discontinuing exenatide if renal dysfunction suspected and cannot be explained by other causes.21 Renal effects usually reversible with supportive treatment and discontinuance of potentially causative agents, including exenatide.1 (See Renal Impairment under Cautions and also see Renal Impairment under Dosage and Administration.)

Macrovascular Outcomes

Evidence of macrovascular risk reduction with exenatide, extended-release exenatide, or any other antidiabetic agent not conclusively demonstrated in controlled clinical trials.138

Risk Associated with Sharing of Injection Pens

Do not share exenatide or extended-release exenatide injection pens among patients, even if the needle has been changed; sharing poses risk for transmission of blood-borne pathogens.1386669

Specific Populations

Pregnancy

Category C.138

Pregnancy registry at 800-633-9081.138

Lactation

Distributed into milk in mice; not known whether distributed into human milk.138 Discontinue nursing or the drug.138

Pediatric Use

Safety and efficacy of exenatide not established in patients <17 years of age.114

Safety and efficacy of extended-release exenatide not established in pediatric patients.38 Use in this patient population not recommended by manufacturer.38

Geriatric Use

No substantial differences in safety and efficacy nor in pharmacokinetics relative to younger adults.1938 Geriatric patients are more likely to have decreased renal function; use caution when initiating drug in such patients.38

Hepatic Impairment

Pharmacokinetics of exenatide or extended-release exenatide not evaluated, but impact of hepatic impairment should be minimal.11438

Renal Impairment

Because exenatide or extended-release exenatide may induce nausea and vomiting with transient hypovolemia, this drug may worsen renal function.138 (See Renal Effects under Cautions.)

Decreased clearance of exenatide in patients with ESRD receiving dialysis; possible decreased tolerance to therapy due to adverse GI effects.112 In such patients, single doses of exenatide 5 mcg were not well tolerated due to adverse GI effects.38 Safety and efficacy of extended-release exenatide not established in patients with ESRD or severe renal impairment.38

Do not use exenatide or extended-release exenatide in patients with ESRD or severe renal impairment (Clcr <30 mL/minute); use with caution in patients who have undergone renal transplantation.192138

Use caution when initiating exenatide or increasing dosage from 5 mcg twice daily to 10 mcg twice daily in patients with moderate renal impairment (Clcr 30–50 mL/minute).11421 Use extended-release exenatide with caution in such patients.38 (See Elimination: Special Populations, under Pharmacokinetics.)

Interactions for Byetta

GI Absorption of Other Drugs

Possible decreased rate and extent of absorption of concomitantly administered oral drugs; use caution with oral drugs that have a narrow therapeutic index or require rapid GI absorption.138

With oral drugs for which efficacy depends on threshold concentrations, administer ≥1 hour before exenatide.19 If such drugs need to be administered with food, administer them with a meal or snack (e.g., lunch) at a time when exenatide is not administered.1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Exenatide: Decreased AUC and peak plasma concentration and increased time to peak plasma concentration of acetaminophen when administered simultaneously with or at 1, 2, or 4 hours after exenatide111

Extended-release exenatide: Acetaminophen AUC not appreciably changed but acetaminophen peak plasma concentration decreased (effect greater in fasting than fed state) and time to peak concentration increased; effects generally less than those observed when acetaminophen given with or 1–4 hours after exenatide13859

Insulin secretagogues, insulin independent

Sulfonylureas: Increased risk of hypoglycemia with exenatide or extended-release exenatide138

Decreased peak plasma concentration and delayed time to peak concentration of digoxin when exenatide administered 30 minutes before digoxin; no change in digoxin steady-state AUC and renal clearance191038

Extended-release exenatide: Safety and efficacy of concurrent insulin not established38

Exenatide: Consider reduced concurrent insulin dosage in patients at increased risk of hypoglycemia; concurrent use of prandial insulin not recommended1

Extended-release exenatide: Concurrent use of insulin not recommended38

Lisinopril

Delayed steady-state time to peak plasma lisinopril concentrations; no change in steady-state AUC or peak plasma lisinopril concentrations or in mean 24-hour SBP and DBP 191338

Lovastatin

Decreased AUC and peak plasma concentration and delayed time to peak plasma concentration of lovastatin when exenatide administered 30 minutes before lovastatin; no consistent changes in lipid profiles1938

Effect of exenatide on ethinyl estradiol/levonorgestrel pharmacokinetics confounded by possible effect of food138

Administer oral contraceptive ≥1 hour before exenatide1

Warfarin

Exenatide: Delayed time to peak plasma concentration of warfarin; no clinically important change in AUC or peak plasma warfarin concentrations or INR; however, some reports of increased INR, sometimes associated with bleeding1138

Extended-release exenatide: Data lacking38

Monitor PT more frequently after initiating or altering exenatide therapy; once a stable PT achieved, PT may be monitored at intervals usually recommended for patients receiving warfarin1

Monitor INR more frequently after initiating extended-release exenatide therapy; once a stable INR achieved, INR may be monitored at intervals generally recommended for patients receiving warfarin38

Byetta Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration of exenatide, peak plasma concentration usually attained in 2.1 hours.1

Absorption of exenatide is similar when injected into abdomen, thigh, or arm.1

Following sub-Q administration of extended-release exenatide, drug is released from the microspheres over approximately 10 weeks.38 Initial release of surface-bound exenatide is followed by gradual release from microspheres; peak concentrations occur at approximately week 2 and week 6–7.38

Inhibits inappropriately high glucagon secretion (e.g., after a meal) in patients with type 2 diabetes mellitus;138 does not impair normal glucagon response to hypoglycemia.138

Slows gastric emptying, which reduces the rate of glucose absorption from a meal, reduces food intake, and is associated with weight loss.1256838

Does not appear to be associated with clinically important prolongation of the corrected QT interval (QTc, Bazett's formula).138

Advice to Patients

Importance of instructing patients on proper use and storage of the exenatide or extended-release exenatide injection pen, including proper reconstitution and injection technique to ensure delivery of a full dose, proper disposal of injection pens and needles using puncture-resistant containers, how and when to set up a new injection pen, and that only one setup step is necessary at initial use of exenatide.1223867686970

Importance of patient reading medication guide and the injection pen user manual before initiating therapy and each time drug is dispensed.12122386667686970

Importance of patients not self-administering exenatide or extended-release exenatide if they are blind or unable to see well.38666769

Importance of informing patients regarding potential risks and advantages of exenatide or extended-release exenatide therapy and of alternative modes of therapy.1223870 Importance of not using exenatide or extended-release exenatide in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1223870

Importance of informing patients that extended-release exenatide causes benign and malignant thyroid C-cell tumors in rats and that the relevance of this finding in humans is unknown.3870 Importance of not using extended-release exenatide in patients with a personal or family history of medullary thyroid cancer (MTC) or diagnosis of multiple endocrine neoplasia syndrome type 2 (MEN 2).3870 Importance of advising patients to report symptoms that may be suggestive of thyroid cancer (e.g., lump or swelling in neck, hoarseness, dysphagia, dyspnea).3870

Importance of patients discontinuing exenatide or extended-release exenatide and other suspect drugs and seeking medical assistance immediately if signs and symptoms of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema) occur.1223870 Importance of patients informing their clinician if they have experienced a sensitivity reaction to exenatide or any ingredient in the formulations.1223870

Importance of informing patient of the potential risk of acute pancreatitis, which may be severe or fatal.117223870 Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or high triglyceride levels.122 Importance of patients discontinuing exenatide or extended-release exenatide and promptly informing clinician if unexplained, persistent, severe abdominal pain that may radiate to the back and may or may not be accompanied by nausea and vomiting occurs.117223870 If pancreatitis is suspected, discontinue exenatide or extended-release exenatide; do not restart if pancreatitis confirmed.117223870

Importance of informing patients of the potential risk for worsening renal function and about signs and symptoms of altered renal function (e.g., increased Scr; changes in color, frequency, amount of urination; unexplained swelling in extremities; increases in BP; lethargy; changes in appetite or digestion; dull ache in the middle to lower back).1213870 Importance of patient informing clinician about development of nausea, vomiting, or diarrhea, which may contribute to dehydration and consequent altered renal function.2122 Importance of informing patients that chronic conditions such as hypertension or pancreatitis and concomitant therapy with NSAIAs, diuretics, or antihypertensive agents can increase the risk of developing altered renal function with exenatide therapy.2122

Importance of informing patients receiving exenatide that the dosage of concomitant insulin may need to be reduced in those at increased risk of hypoglycemia.122

Increased risk of hypoglycemia when exenatide or extended-release exenatide is used with an agent that induces hypoglycemia, such as a sulfonylurea12238 or other glucose-independent insulin secretagogue (e.g., meglitinide);1223870 lower dosage of sulfonylurea or other insulin secretagogue may be required to reduce risk of hypoglycemia.12238

Importance of reviewing with patients the symptoms, treatment, and conditions that predispose to development of hypoglycemia when initiating exenatide or extended-release exenatide treatment, especially when exenatide is used with a sulfonylurea or insulin; importance of clinician reinforcing instructions for management of hypoglycemia.12238

Importance of advising patient to seek medical advice if symptomatic sub-Q nodules or any signs or symptoms of abscess, cellulitis, or necrosis occur.38

Importance of informing patients that reduced appetite, food intake, and/or body weight may occur with exenatide or extended-release exenatide therapy but do not require modification of dosage regimen.12238 Importance of informing patient about occurrence of nausea, particularly upon initiation of exenatide or extended-release exenatide therapy, and that nausea decreases over time as the drug is continued.1223870

Importance of informing patients that injection pens should not be shared with another person, even if the needle has been changed.122386669 Such sharing may pose a risk of transmitting or acquiring infection.122386669

Importance of advising patients what to do if a dose of exenatide or extended-release exenatide is missed.1223870 (See Administration under Dosage and Administration.)

Importance of injecting extended-release exenatide immediately after reconstitution.3870 Importance of not injecting exenatide or extended-release exenatide IV or IM.13870

Importance of informing patient to administer extended-release exenatide at any time on the dosing day, with or without meals.3870 The day of once-weekly administration (once every 7 days) can be changed if necessary, provided the last dose was administered 3 or more days previously.38

Importance of informing patients to discontinue exenatide once extended-release exenatide is initiated.38 Importance of informing patients that transient elevations in blood glucose concentrations may occur but generally improve within the first 2 weeks after initiation of extended-release exenatide therapy.38

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1223870 Importance of informing women about enrolling in the pregnancy registry for exenatide or extended-release exenatide if they use the drugs at any time during pregnancy.1223870

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., hypertension, history of liver disease, gastroparesis or serious digestive problems, severe kidney disease or kidney transplant).121223870

Importance of informing patients of other important precautionary information.138 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.